Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation

Pariollaud, Marie and Gibbs, Julie E. and Hopwood, Thomas W. and Brown, Sheila and Begley, Nicola and Vonslow, Ryan and Poolman, Toryn and Guo, Baoqiang and Saer, Ben and Jones, D. Heulyn and Tellam, James P. and Bresciani, Stefano and Tomkinson, Nicholas C.O. and Wojno-Picon, Justyna and Cooper, Anthony W.J. and Daniels, Dion A. and Trump, Ryan P. and Grant, Daniel and Zuercher, William and Willson, Timothy M. and MacDonald, Andrew S. and Bolognese, Brian and Podolin, Patricia L. and Sanchez, Yolanda and Loudon, Andrew S.I. and Ray, David W. (2018) Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation. Journal of Clinical Investigation, 128 (6). pp. 2281-2296. ISSN 0021-9738

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    Abstract

    Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBα as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBß in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERBα plays the dominant role, as deletion of REV-ERBß alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBα protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERBα protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV-ERBα in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBα protein couple the core clock to innate immunity.